Dipeptidyl peptidases, enzymes that catalyze the hydrolysis of polypeptides to release dipeptides, play important roles in physiological and pathological processes. Dipeptidyl peptidases IV (DPP-IV) and fibroblast activation protein (FAP) are two well-known members of the dipeptidyl peptidases family.
DPP-IV degrades glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide hormones produced by intestinal endocrine L-cells in response to nutrient ingestion. Inhibiting DPP-IV enhances insulin secretion, lowers blood sugar levels, and improves pancreatic β-cell function. Deacon C. et al., Expert Opin. Investig. Drugs 2007 16: 533-545 and Deacon C. Curr. Opin. Investig. Drugs 2008, 9: 402-413. The DPP-IV inhibition is well tolerated and does not cause hypoglycemia or increase body weight in human. Deacon C. Curr. Opin. Investig. Drugs 2008, 9: 402-413 and Rosenstock J. et al., Diabetes Obes. Metab. 2008, 10: 376-386. Thus, inhibitors of DPP-IV are potential drug candidates for type-II diabetes. See, e.g., Pederson R. et al., Diabetes 1998, 47: 1253-1258; Ahren B. et al., Diabetes Care 2002, 25: 869-875; Deacon C. et al., Expert Opin. Investig. Drugs 2004, 13:1091-1102; and Pei Z. Curr. Opin. Drug Discov. Devel. 2008, 11: 512-532.
FAP is exclusively expressed in fetal cells, wounded tissue, and stromal fibroblasts in most malignant epithelial tumors. See Scanlan M. et al., Proc. Natl. Acad. Sci. U.S.A 1994, 91: 5657-5661; Rettig W. et al., Proc. Natl. Acad. Sci. U.S.A 1988, 85: 3110-3114; and Huber M. et al., J. Invest. Dermatol. 200, 120: 182-188. Studies show that xenografted mice with constitutively expressed FAP were 2-4 folds more likely to develop tumors than the mock-transfection and demonstrated 10-40 fold tumor growth than the control mice. See Cheng J. et al., Cancer Res. 2002, 62: 4767-4772. When the xenografted mice were treated with anti-FAP antisera, the tumor growth was attenuated. Human clinical trials show that patients whose colon tumors had high levels of stromal FAP were more likely to have aggressive disease progression and potential development of metastases or recurrence. See Henry L. et al., Clin. Cancer Res. 2007, 13: 1736-1741. Thus, anti-FAP agents can be used to treat cancers.
In addition, FAP is also highly expressed in fibroblast-like synoviocytes from rheumatoid arthritis (RA) and osteroarthritis (OA) patients. Bauer S. et al., Arthritis Res. Ther. 2006, 8: R171. It is therefore suggested using FAP as a therapeutic target to treat RA or OA.